Molecular imaging of factor XIIIa activity in thrombosis using a novel, near-infrared fluorescent contrast agent that covalently links to thrombi

Farouc A. Jaffer, Ching Hsuan Tung, Joanna J. Wykrzykowska, Nan Hui Ho, Aiilyan K. Houng, Guy Reed, Ralph Weissleder

Research output: Contribution to journalArticle

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Abstract

Background - Activated factor XIII (FXIIIa) mediates fibrinolytic resistance and is a hallmark of newly formed thrombi. In vivo imaging of FXIIIa activity could further elucidate the role of this molecule in thrombosis and other biological processes and aid in the clinical detection of acute thrombi. Methods and Results - An FXIIIa-sensitive near-infrared fluorescence imaging agent (A15) was engineered by conjugating a near-infrared fluorochrome to a peptide ligand derived from the amino terminus of α2- antiplasmin. To evaluate the molecular specificity of A15 for FXIIIa, a control agent (C15) was also synthesized by modifying a single key glutamine residue in A15. Fluorescence imaging experiments with A15 demonstrated stronger thrombosis enhancement in human plasma clots in vitro (P<0.001 versus C15 clots and other controls). A15 was found to be highly specific for the active site of FXIIIa and was covalently bound to fibrin. In vivo murine experiments with A15 demonstrated significant signal enhancement in acute intravascular thrombi (P<0.05 versus C15 group). Minimal A15 enhancement was seen in older aged thrombi (>24 hours), consistent with an expected decline of FXIIIa activity over time. Imaging results were confirmed on correlative histopathology and fluorescence microscopy. Conclusions - A15 is a novel optical imaging agent that is specifically crosslinked to fibrin by FXIIIa, permitting detection of FXIIIa activity in experimental thrombi in vivo. This agent should permit assessment of FXIIIa activity in a broad range of biological processes and could aid in the clinical diagnosis of acute thrombi.

Original languageEnglish (US)
Pages (from-to)170-176
Number of pages7
JournalCirculation
Volume110
Issue number2
DOIs
StatePublished - Jul 13 2004

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Factor XIIIa
Molecular Imaging
Fluorescent Dyes
Contrast Media
Thrombosis
Optical Imaging
Biological Phenomena
Antifibrinolytic Agents
Fibrin
Glutamine
Fluorescence Microscopy
Ligands
Peptides

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Molecular imaging of factor XIIIa activity in thrombosis using a novel, near-infrared fluorescent contrast agent that covalently links to thrombi. / Jaffer, Farouc A.; Tung, Ching Hsuan; Wykrzykowska, Joanna J.; Ho, Nan Hui; Houng, Aiilyan K.; Reed, Guy; Weissleder, Ralph.

In: Circulation, Vol. 110, No. 2, 13.07.2004, p. 170-176.

Research output: Contribution to journalArticle

Jaffer, Farouc A. ; Tung, Ching Hsuan ; Wykrzykowska, Joanna J. ; Ho, Nan Hui ; Houng, Aiilyan K. ; Reed, Guy ; Weissleder, Ralph. / Molecular imaging of factor XIIIa activity in thrombosis using a novel, near-infrared fluorescent contrast agent that covalently links to thrombi. In: Circulation. 2004 ; Vol. 110, No. 2. pp. 170-176.
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AU - Wykrzykowska, Joanna J.

AU - Ho, Nan Hui

AU - Houng, Aiilyan K.

AU - Reed, Guy

AU - Weissleder, Ralph

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N2 - Background - Activated factor XIII (FXIIIa) mediates fibrinolytic resistance and is a hallmark of newly formed thrombi. In vivo imaging of FXIIIa activity could further elucidate the role of this molecule in thrombosis and other biological processes and aid in the clinical detection of acute thrombi. Methods and Results - An FXIIIa-sensitive near-infrared fluorescence imaging agent (A15) was engineered by conjugating a near-infrared fluorochrome to a peptide ligand derived from the amino terminus of α2- antiplasmin. To evaluate the molecular specificity of A15 for FXIIIa, a control agent (C15) was also synthesized by modifying a single key glutamine residue in A15. Fluorescence imaging experiments with A15 demonstrated stronger thrombosis enhancement in human plasma clots in vitro (P<0.001 versus C15 clots and other controls). A15 was found to be highly specific for the active site of FXIIIa and was covalently bound to fibrin. In vivo murine experiments with A15 demonstrated significant signal enhancement in acute intravascular thrombi (P<0.05 versus C15 group). Minimal A15 enhancement was seen in older aged thrombi (>24 hours), consistent with an expected decline of FXIIIa activity over time. Imaging results were confirmed on correlative histopathology and fluorescence microscopy. Conclusions - A15 is a novel optical imaging agent that is specifically crosslinked to fibrin by FXIIIa, permitting detection of FXIIIa activity in experimental thrombi in vivo. This agent should permit assessment of FXIIIa activity in a broad range of biological processes and could aid in the clinical diagnosis of acute thrombi.

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